TMAO Activates Carotid Endothelial Inflammasomes Leading to Enhanced Neointimal Formation in Nlrp3 Mice
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Recent studies have shown that gut microbial metabolite, trimethylamineNOxide (TMAO), is a biomarker for atherosclerosis. However, the mechanisms of how TMAO induces atherosclerosis are still unclear. The present study tested whether TMAO induces Nlrp3 inflammasome activation and consequent endothelial injury leading to atherosclerotic lesion development in the carotid arterial wall. Confocal microscopy showed that colocalization of Nlrp3 with ASC significantly increased in the intima of the carotid arteries of TMAOtreated Nlrp3+/+ mice, suggesting the formation of Nlrp3 inflammasomes in the endothelium of these arteries. In Nlrp3/ mice, however, such colocalization was much less detected. In consistent with inflammasome formation, TMAOinduced IL1 production in the intima was abolished in Nlrp3/ mice. Furthermore, we found that TMAO treatment decreased ZO2, VEcadherin and occuludin expression in carotid arteries of Nlrp3+/+ mice but not in Nlrp3/ mice, signifying tight junction disruption in the carotid arteries of Nlrp3+/+ mice. In addition, we found that TMAO treatment had significantly increased vascular permeability to intravenously injected Evans blue dye compared to vehicle treated Nlrp3+/+ mice. However, such TMAOinduced vascular permeability was attenuated in Nlrp3/ mice, suggesting that Nlrp3 inflammasome activation plays an important role in TMAOinduced vascular leakage in mouse hearts. Furthermore, we also found that TMAO markedly increased neointimal formation in partially ligated left carotid arteries (PLCA) of Nlrp3+/+ mice. However, such TMAOenhanced neointimal formation and increased I/M ratio in PLCA was markedly attenuated in Nlrp3/ mice. These results suggest that the formation and activation of NLRP3 inflammasomes by TMAO may be an important mechanism in initiating endothelial inflammatory response leading to arterial inflammation and endothelial dysfunction and consequent atherosclerosis in mice.Support or Funding InformationR01DK104031 and R56HL143809
